SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis, 2025, Moreau, Fluge, Mella et al

Nightsong

Nightsong

Senior Member (Voting Rights)
Abstract:

Background​

Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.

Methods​

A case–control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors—vildagliptin, saxagliptin, and linagliptin—on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.

Results​

ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.

Conclusions​

SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.

Link | PDF (J. Transl. Med, July 2025, open access)
 
Nightsong said:
Abstract:

Background​

Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.

Methods​

A case–control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors—vildagliptin, saxagliptin, and linagliptin—on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.

Results​

ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.

Conclusions​

SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.

Link | PDF (J. Transl. Med, July 2025, open access)
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I saw Moreau talk about this in an interview recently, didn't know Fluge and Mella were involved though. Very interested to know what others think.

Nightsong said:
Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.
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Is there a word missing at the end here? I can't quite parse it.
 
From Google AI
SMPDL3b and Insulin Receptor Signaling:
SMPDL3b is found in lipid rafts of cell membranes, and its presence can impact the fluidity of these membranes. In podocytes, SMPDL3b excess can hinder the insulin receptor's ability to signal effectively, particularly the isoform B (IRB).
pubmed.ncbi.nlm.nih.gov

SMPDL3b modulates insulin receptor signaling in diabetic kidney disease - PubMed

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Could this be a link to the Beetjes et al Biobank findings of altered glucose and insulin signalling?
 
It does look interesting from the abstract:
  • some decent researchers involved.
  • Two good sized cohorts, one with controls.
  • A coherent story of increased serum levels of SMPDL3B in the blood, and less in the membranes of monocytes.
  • Gene expression matches the measured molecule levels, with a corroborating increase in a molecule that could explain the increased cleavage of SMPDL3B from cells and into the serum.
  • and a plausible reason for increased disease prevalence in females.
 
It seems like some charts are missing from figure 2. The caption talks about fig 2a through 2n, but I only see 2a through 2g. And 2b through 2g in the image seem to correspond to 2i through 2n in the caption, with 2b through 2h missing.

1751933643138.png
Influence of covariates on plasma SMPDL3B levels and symptom severity in ME patients. a Plasma levels of SMPDL3B in ME patients (n = 249) and healthy controls (n = 63) from the Canadian cohort. Plasma SMPDL3B levels in Canadian cohort, stratified by SMPDL3B levels using a threshold of 30 ng/mL (n = 118 and n = 131), showing the physical scores of SF-36 questionnaire (b), reduced activity scores of MFI-20 questionnaire (c), PEM scores of DSQ questionnaire (d), severity scores of MFI-20 questionnaire (e), cognitive exhaustion score of DPEMQ questionnaire (f), pain or aching in your muscles score of DSQ questionnaire (g), and the bladder problems score of DSQ questionnaire (h). i Plasma levels of SMPDL3B in different groups of patients with ME from the Norwegian cohort grouped by symptom severity (n = 16 for mild, n = 40 for mild/moderate, n = 41 for moderate, n = 22 moderate/severe and n = 21 severe). Disease severity was determined based on clinical assessments incorporating standardized and trial-specific questionnaires. j Plasma SMPDL3B levels in ME Canadian, ME Norwegian and healthy control female participants (n = 208, n = 119 and n = 33 respectively) and males (n = 41, n = 22 and n = 30 respectively). k Plasma concentrations of SMPDL3B in Canadian female ME participants across different age groups (n = 16 for 18–30 years, n = 97 for 31–50 for years, n = 95 for 51 years and up). l Plasma concentrations of SMPDL3B in Norwegian female ME participants across different age groups (n = 37 for 18–30 years, n = 65 31–50 for years, n = 16 for 51 years and up). m Plasma levels of SMPDL3B in Canadian female participants with or without oral contraceptive use (n = 176 and n = 32 respectively). n Plasma levels of SMPDL3B in Norwegian female participants with or without oral contraceptive use (n = 88 and n = 31 respectively). An unpaired T test was performed when comparing two groups. For comparisons between two groups, the Mann–Whitney U test was used. For comparisons involving more than two groups, the Kruskal–Wallis test was performed, followed by Dunn’s post hoc test with multiple comparison correction where appropriate. Differences were found to be significant at *P < 0.05, **P < 0.01, *** P-value < 0.001 and ****P < 0.0001
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Mij said:
Does this have a connection to Rituximab and muscle mito function in some way?
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Rituximab binds to SMPDL3B in muscle.

See A novel estrogen receptor 1: sphingomyelin phosphodiesterase acid-like 3B pathway mediates rituximab response in myositis patients (2022)

In addition to B-cell depletion, rituximab may be beneficial in myositis due to increased ESR1 signalling mediated by rituximab binding to SMPDL3B on skeletal muscle cells.
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EDIT: I see that is actually referenced in this thread's paper as [28] —

This paper said:
Similarly, studies on SMPDL3B’s role in prostate and ovarian cancers suggest distinct sex-specific regulatory mechanisms, including interactions with estrogen receptors [27–29].
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Last edited:
BrightCandle said:
"specificity of 87% and a sensitivity of 77%"
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I think the specificity and sensitivity percentages are fine - although I don't know yet what was included in the model producing them. Not everyone on the ME/CFS cohorts will have ME/CFS. There may be other reasons for the molecules to differ in values, even in healthy controls.

But, I agree, the Figure 2 charts of plasma SMPDL3B are rather unconvincing.
 
@forestglip Can you email Moreau?

Not so encouraging that the 13 authors didn’t review the proofs (as well as the journal editors)— this isn’t a preprint.



forestglip said:
It seems like some charts are missing from figure 2. The caption talks about fig 2a through 2n, but I only see 2a through 2g. And 2b through 2g in the image seem to correspond to 2i through 2n in the caption, with 2b through 2h missing.
Click to expand...
 
forestglip said:
It seems like some charts are missing from figure 2. The caption talks about fig 2a through 2n, but I only see 2a through 2g. And 2b through 2g in the image seem to correspond to 2i through 2n in the caption, with 2b through 2h missing.
Click to expand...
I was shocked when I saw the label too. Figure 2 (SMPDL3B levels) looks very underwhelming, perhaps skewed by birth control.

In Figure 3H, the LPS dose response curve is up and down.

In Figure 4, a lot of the dose response curves are not linear????

In Figure 5, some of the vehicle experiments have huge spread. That shouldn't be the case for the control experiment should it? If an experiment has a large spread it should be repeated many many more times to allow use of comparison.

I'm not so excited anymore.
 
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